Treating brain pathologies, including cancer, is particularly difficult due to the isolation of the brain by the blood-brain barrier (BBB). The BBB restricts or blocks the penetration of therapeutic agents (depending on type) to the brain, making it difficult to treat varying conditions (e.g. brain...

Treating brain pathologies, including cancer, is particularly difficult due to the isolation of the brain by the blood-brain barrier (BBB). The BBB restricts or blocks the penetration of therapeutic agents (depending on type) to the brain, making it difficult to treat varying conditions (e.g. brain tumor). This limits options for treatment and necessitates the use of high or even extreme doses of drugs in the treatment of patients. Consequently, agents that transiently disrupt the BBB and allow safe passage of drugs to the brain would be useful for a variety of neuropathologies.

The present invention uses modified human serum albumin (HSA) in order to induce transient breakage of the BBB. Modified HSA can be used in combination with other agents, such as chemotherapeutic drugs, in order to increase their entrance to the brain. Thus, lower concentration of drugs can be used, while increasing treatment efficacy.

Applications

·Minimally-invasive, local, non-toxic  high efficacy of action when using convection-enhanced delivery with no post-treatment toxicity.

·Approved treatment  HSA is already an approved drug for various medical conditions.

·Can be combined with other drugs, such as chemotherapeutic agents.

Technology's Essence

A collaboration between the Sheba Medical Center and Weizmann Institute of Science, Israel, found that modified human serum albumin can induce BBB breakage in a transient manner and with low toxicity to the brain. The research groups screened multiple modified HSAs in vitro and selected the most efficient one. In vivo experiments in rats bearing glioma brain tumors showed that administration of this modified HSA along with chemotherapy reduced tumor size. No hemorrhages or toxicity post-treatment were detected, and the BBB was completely recovered after 7 days.

Senescence is a form of cell-cycle arrest which occurs in many cell types. Cellular senescence can reduce tissue damage and tumorigenesis; however long-term induction of senescence promotes fibrosis, metastasis, inflammation, tissue damage and tissue aging. Senescent cells are known to be involved in...

Senescence is a form of cell-cycle arrest which occurs in many cell types. Cellular senescence can reduce tissue damage and tumorigenesis; however long-term induction of senescence promotes fibrosis, metastasis, inflammation, tissue damage and tissue aging. Senescent cells are known to be involved in many disorders and pathologies  from cancer to hair loss. Identification and elimination of senescent cells may thus be beneficial for a variety of diseases.

Prof. Krizhanovsky and his team performed clever proteomic studies and discovered surface markers that are unique to senescent cells of the fibrotic tissue. These cell surface markers which differentiate senescent cells from non-senescent cells can be utilized for antibody mediated elimination of these cells, with the goal of treating fibrotic disease.

Applications

* Novel cell surface markers of senescent cells

* Treat senescence-related diseases

Advantages

Prof. Krizhanovsky's team induced senescence in vitro by DNA damage (DIS) or oncogenes (OIS) and explored proteins expressed on these senescent cells by mass spectrometry. Then a panel of cell-surface proteins which identified the senescent cells was assembled and verified in vivo. Among these proteins, protein "X" was further studied and found to be senescent-cell specific. The group currently attempts to determine its biological role and develop a targeting antibody to protein X.

Analysis of the transcriptome of cells can inform greatly about the state of said cells, including maturation, activation, transformation, etc. Therefore it would be of great research and clinical value to analyze transcriptomes of different cell populations and to compare gene expression on large...

Analysis of the transcriptome of cells can inform greatly about the state of said cells, including maturation, activation, transformation, etc. Therefore it would be of great research and clinical value to analyze transcriptomes of different cell populations and to compare gene expression on large scales. A particularly useful method would be Next Generation Sequencing (NGS) as it allows parallel sequencing in high sensitivity, reducing cost and time. However, NGS requires special protocols and preparation procedures in order to ensure a high quality and unbiased analysis.

The lab of Prof. Amit has developed a high-throughput system using tools, techniques, and kits for analyzing transcriptomes by NGS for analysis of gene expression. From the initial stage of cell preparation all the way to library generation, those innovative methods contribute to the power of NGS and provide effective tools to study cellular processes with a high-quality output.

Applications

* Novel method

* Multiple applications whether comparing cell states or different pathologies

* Unbiased analysis of different cell types

Technology's Essence

Prof. Amit and his lab members developed an automated framework which enables sequencing transcriptomes of single cells or cell populations. This framework includes the extraction of RNA from the isolated cells, RNA fragmentation, and cDNA production. Ultimately, libraries are created which include various additions such as barcodes and adapters and can be sequenced to provide comprehensive insight on gene expression within the cells.

The treatment of respiratory conditions is currently one of the major challenges to health care systems all over the world. The problem is that most therapeutics currently available for treating pulmonary indications are non-curative, and simply improve symptoms. Presently the only cure for late stage...

The treatment of respiratory conditions is currently one of the major challenges to health care systems all over the world. The problem is that most therapeutics currently available for treating pulmonary indications are non-curative, and simply improve symptoms. Presently the only cure for late stage pulmonary diseases is a lung transplant, which includes its own host of problems ranging long waitlists to lifelong immunosuppression. These issues explain why pulmonary diseases represent the second leading cause of death in the world. Therefore, a strong need exists for alternative therapeutic options in treating pulmonary related diseases.

Prof. Yair Reisner and his research group have developed a unique set of methods for culturing and transplanting cells for use in treating respiratory illnesses. Their innovation was not simply an improvement in terms of symptoms but actually showed effective lung repair in mouse models.

Applications

?Treatment of lung indications

?Protocol developed such that the method is compatible with donor (allogeneic) cells

Technology's Essence

The Reisner research group has developed two methods for cell transplantation to repair pulmonary diseases. The first method involves incubating a suspension of fetal pulmonary tissue that is developed to a gestation period of about 20-22 weeks. The reason being is that this acts as the optimal gestation window, where the cells show the high amount of different types of pulmonary progenitor cells. When transplanted into lung damaged mouse models, the cells differentiated and incorporated themselves into the lung, forming fully functional units.

The second method involves sourcing a specific hematopoietic stem cell population from fetal lung. Following a thorough understanding of the therapeutic potential of the cells, in their capacity to develop into the desired lineages. The Reisner group developed a protocol in which the transplantation of allogeneic cells was feasible but did not require long-term immunosuppression. Such that the mouse models showed an ability to develop immunotolerance to said donor cells, and achieved lung repair.

Obesity is the health epidemic of the modern world, with nearly half the global adult population being categorized as obese. The consequences of said mass obesity is that it is overwhelming the medical systems all over the world, as obesity is linked to numerous diseases ranging from diabetes to cancer...

Obesity is the health epidemic of the modern world, with nearly half the global adult population being categorized as obese. The consequences of said mass obesity is that it is overwhelming the medical systems all over the world, as obesity is linked to numerous diseases ranging from diabetes to cancer. The challenge is not only in reducing obesity through weight loss programs, be it via dietary programs, bariatric surgery, and so on. The issue is in ensuring that the weight loss remains, as nearly 80% of those with successful initial weight loss, relapse to their previous obese state or worse. Consequently, there is a fundamental need to treat individuals to ensure that reduction of weight is maintained.

The collaborative efforts of Prof. Eran Segal and Prof. Eran Elinav have led to an innovation by understanding the gut microbiome. Whereby understanding the microbial population of the intestinal tract can be used to diagnose for future obesity relapse and possible bacterial populations and/or chemical agents that can assist in stopping weight gain.

Applications

Diagnostic to test which populations are more susceptible to relapsed obesity

A method of either using an agent or a specific bacterial population to reduce relapsed obesity

Technology's Essence

The research teams of Profs. Segal and Elinav investigated the role of the gut microbiome in obesity relapse. Using mouse models where they cycle between weight loss and weight gain, it was noted that gut microbial populations were altered after weight gain. Even after cycling to weight loss, said mice retained a microbial memory, such that specific populations of bacteria were indicative of weight re-gain. By using said bacterial populations, it is possible to diagnose and determine whom is most susceptible to relapsing obesity even after weight loss programs. Additionally, they discovered that maintaining or boosting certain bacterial populations can act as a method to ameliorate obesity relapse.

TNBC is a highly aggressive form of breast cancer, which is characterized by absence of the estrogen and progesterone receptors and lack of HER2 amplification. TNBC is associated with poor prognosis and has no effective targeted treatment. EGFR is highly expressed in ~50% of TNBC patients, and though it is considered a therapeutic target, targeting EGFR alone does not improve the clinical outcome of TNBC. As there is likely compensatory signaling by other molecules that bypass EGFR inhibition.

The group of Prof. Sima Lev has found a method to inhibit EGFR as well as two members of the Fak family kinases, namely PYK2 and FAK. By using extensive in vitro and in vivo work, the group managed to show that combined inhibition of EGFR and FAK/PYK2 obstructs TNBC growth.

Applications

Combined inhibition of kinases leads to a novel mechanism with beneficial synergistic effects.

Advantages

Technology's Essence

Prof. Lev's research group discovered that targeting FAK/PYK2 in different triple negative breast cancer (TNBC) cell lines reduced cellular growth. Therefore, they examined the effect of targeting FAK/PYK2 by shRNA or commercially available inhibitors as well as inhibiting EGFR by small molecules that are used to treat EGFR-related cancers. In vitro essays showed that combined inhibition of EGFR and FAK/PYK2 significantly reduced proliferation of TNBC basal-like cell lines, compared to EGFR inhibition alone. The group next tested the effect of PYK2 knock-down and EGFR inhibition by the drug gefitinib in vivo in a xenograted mouse model, which led to a significant reduction of tumor size by 30-40%.

Numerous medical conditions are related to inflammation, such as pancreatitis, psoriasis, inflammatory bowel disease, atherosclerosis, neurodegeneration, and more. However, determination of inflammation in the body, especially at early stages of a pathology is difficult to assess. Therefore, there is a...

Numerous medical conditions are related to inflammation, such as pancreatitis, psoriasis, inflammatory bowel disease, atherosclerosis, neurodegeneration, and more. However, determination of inflammation in the body, especially at early stages of a pathology is difficult to assess. Therefore, there is a great clinical need for diagnostic tools to gauge inflammation.

The team of Prof. David Wallach have discovered novel biomarkers in exosomes related to necroptosis, a form of programmed cell death that induces inflammation. Using these biomarkers in exosomes different diagnostic tests can be developed for an array of inflammatory conditions.

Applications

?Diagnostics for inflammation

?Specificity in terms of tissue affected when combined with other biomarkers

Technology's Essence

Cell-derived vesicles termed exosomes are commonly found in bodily fluids such as blood and urine. Consequently, by examining these exosomes it is feasible to discover different biomarkers for the state of health in the human body. The Wallach team discovered that when the kinase RIPK3 is activated, a known inducer of inflammation and necroptosis, it also phosphorylates mixed lineage kinase domain like pseudokinase (MLKL) as one of its targets. Phosphorylated MLKL was then shown to increase exosome production, which led to a greater release of phosphorylated MLKL in said exosomes. Therefore using in vitro work the Wallach team was able to show that screening exosomes for phosphorylated MLKL represents a potential diagnostic for inflammation.

Jet lag is a ubiquitous problem for air travelers. As the process of rapidly shifting time zones leads to the bodys circadian rhythm being out of sync to the destinations time schedule. This has a variety of impacts on the body, in particular the general and pervasive feeling of exhaustion, limiting...

Jet lag is a ubiquitous problem for air travelers. As the process of rapidly shifting time zones leads to the bodys circadian rhythm being out of sync to the destinations time schedule. This has a variety of impacts on the body, in particular the general and pervasive feeling of exhaustion, limiting an individuals capacity to function, until acclimation. Therefore travelers, and especially business travelers, have a need for a method to help them prevent or overcome their jet lag rapidly.

The group of Prof. Gad Asher has discovered that specific oxygen conditions can help to rapidly overcome the symptoms of Jet Lag. The technology can be further developed into a device that can be used to treat individuals before and during flights to reduce jet lag.

Applications

Reduction of symptoms of Jet Lag

Technology's Essence

The basis of the discovery by the Asher group is examining and applying the role of oxygen to regulating the circadian rhythm. Experimenting both in vitro and in vivo in animal models, it was found that oxygen is an important regulator of the circadian rhythm. The mediation of oxygen as a circadian rhythm regulator is performed by HIF1? (hypoxia inducible factor 1?). In mouse models the Asher group found that a reduction of oxygen from 21% to ~16-14% led to an accelerated adaptation to Jet-lag like conditions. Simple human studies can be performed so as to translate these important findings.

Treatment of multiple types of oncological malignancies, such as breast cancer involves the targeting one the of HER (EGFR/ErbB) family receptor tyrosine kinases. The challenge that arises in using a specific HER receptor for therapeutic applications is that the cancer can develop resistance to said...

Treatment of multiple types of oncological malignancies, such as breast cancer involves the targeting one the of HER (EGFR/ErbB) family receptor tyrosine kinases. The challenge that arises in using a specific HER receptor for therapeutic applications is that the cancer can develop resistance to said treatment. This tolerance arises due to compensatory mechanisms, such as the activation of alternate HER receptors. Consequently, there is a strong need to develop treatments that target HER receptors outside of the ubiquitously targeted HER1 and 2. In many cases it is HER3 which is responsible for such emergence of resistance.

The group of Prof. Yosef Yarden have developed a novel high affinity anti-HER3 antibody, to act either as an individual anti-cancer treatment or in combination with other therapies.

Applications

Cancer therapy

Diagnostic tool

Technology's Essence

Prof. Yardens research group has developed a high affinity anti-HER3 antibody with a Kd in the range of 10 nM. The group tested the effectiveness of the antibody (termed N33) both in vitro and in xenografts. In all tested cases the anti-HER3 antibody showed promising effects in stopping cancer cell line growth and reducing tumor volume in mouse models.

Alzheimer's disease, as well as other neurodegenerative disorders are characterized by damage to brain tissue. Immune cells within the brain participate in disease progression, whether by slowing it down or escalating disorders severity. Microglia are immune cells that reside within the central nervous...

Alzheimer's disease, as well as other neurodegenerative disorders are characterized by damage to brain tissue. Immune cells within the brain participate in disease progression, whether by slowing it down or escalating disorders severity. Microglia are immune cells that reside within the central nervous system (CNS) and participate in immune activity, particularly phagocytosis. As such, microglia can either contribute to or inhibit Alzheimer's progression, and manipulating them may provide a unique therapeutic option to treat Alzheimer's and other CNS-related disorders.

The groups of Profs. Ido Amit and Michal Schwartz used innovative single cell sequencing technologies in order to characterize these microglias and consequently discovered a series of potential immune checkpoints. Therefore, modulating these checkpoint targets could be a treatment for Alzheimer's disease and other diseases that are related to microglia dysfunction.

Applications

Neurodegenerative diseases

Microglia-related disorders

Novel Targets

Advantages

The Amit and Schwartz groups widely characterized DAMs by single-cell sequencing techniques and found a number of molecules that participate in their immune function. These DAMs were found not only in brains of mouse Alzheimer's model, but also in brains of humans with Alzheimer's that were analyzed post-mortem. The group also expanded the research to other neurodegenerative diseases in mice models, and confirmed DAM presence in these models as well. Therefore, these DAM regulatory molecules hold potential as treatment for a number of neurodegenerative.

The proper functioning of the central nervous system (CNS) depends on effective communication between different neurons. A fundamental process ensuring said communication is myelination, which acts to insulate projections of neurons (axons) to ensure efficient transmittance of electrical impulses....

The proper functioning of the central nervous system (CNS) depends on effective communication between different neurons. A fundamental process ensuring said communication is myelination, which acts to insulate projections of neurons (axons) to ensure efficient transmittance of electrical impulses. Disruption of myelination is connected to numerous serious and debilitating neurological conditions such as multiple sclerosis, Guillain-Barre Syndrome, and others. Therefore, a strong need exists for treating myelination related conditions.

The group of Prof. Elior Peles, have discovered a novel target that regulates development of myelination in oligodendrocytes, G Protein-Coupled Receptor 37 (GPR37). And that modulating GRP37 during later stages of oligodendrocytes they were able to achieve hypermyelination.

Applications

Novel Target

Technology's Essence

The Peles team have found through extensive in vitro and in vivo work that GRP37 negatively regulates oligodendrocyte differentiation and myelination. Consequently, by modulating GRP37 or up regulating a protein transcriptional factor ERKl/2 that is suppressed downstream of GRP37, they could potentially induce or re-establish myelination.

One of the challenges in the areas of synthetic biology and its clinical applications, is the capacity to control the induction of different genes, whether for the purpose of activating genetic circuits or inducing the expression of a specific protein. Present approaches are limited to the number of...

One of the challenges in the areas of synthetic biology and its clinical applications, is the capacity to control the induction of different genes, whether for the purpose of activating genetic circuits or inducing the expression of a specific protein. Present approaches are limited to the number of systems available, inconsistent behavior among systems, and requiring high concentrations of signaling molecule.

A paradigm-shifting discovery by the research team led by Prof. Rotem Sorek, published in the prestigious journal of Nature[1], reveals a new system, termed Arbitrium, which can effectively control gene expression. The basis of the discovery is that phages (viruses) have a quorum sensing system, similar to that found in bacteria, that communicates information to help determine whether a lytic or lysogenic cycle is to be entered. The Arbitrium system has numerous biotechnological and synthetic biology applications, and functions as a new- generation of easy-to-control genetic switches, to induce or shut off the expression of different genes.

Technology's Essence

The research group led by Prof. Rotem Sorek from the Weizmann Institute of Science (WIS) has discovered a novel family of expression systems. The basis of said expression systems is that a six (6) amino acid peptide binds a transcription factor (TF), inhibiting it. The peptide/TF system is shown to be sequence specific, such that a TF only responds to its corresponding peptide. Additionally, each peptide/TF pair only activates an explicit promoter. The Sorek group has discovered over 100 unique peptide/TF pairs, each with a specific TF that binds a specific peptide sequence. Consequently, this generates a large array of orthogonal transcription systems that have a standardized dynamic range and expression profile. This system could be used in the design and control of gene expression across both prokaryotic and eukaryotic systems, as well as applications in controlling genome editing.

Inflammatory bowel disease (IBD), including Crohns disease and ulcerative colitis, is known for causing a dramatic reduction in patients' quality of life. Apart from symptoms such as diarrhea, abdominal pain, and vomiting, IBD can lead to more serious complications such as higher risk of colon cancer...

Inflammatory bowel disease (IBD), including Crohns disease and ulcerative colitis, is known for causing a dramatic reduction in patients' quality of life. Apart from symptoms such as diarrhea, abdominal pain, and vomiting, IBD can lead to more serious complications such as higher risk of colon cancer, bowel obstructions, and other possible debilitating and life-threatening conditions. Presently there is no optimal treatment for IBD, with most treatments presenting different limitations and concerns. Anti-inflammatory drugs, immune-suppressing agents, and antibiotics can relieve some symptoms connected to IBD, but are not treating the primary cause of the disease and include serious side effects. For severe cases, the last resort can be surgical removal or widening of the intestine.

The present technology from the group of Prof. Ayelet Erez offers a novel and effective method for alleviating IBD, based on a deep understanding of the mechanism of action of the pathology. Treatment involves the use of commonly available nutraceuticals, Citrulline and Fisetin, which help to utilize specific metabolic pathways to ameliorate the symptoms connected to IBD. Consequently, this technology represents a data-driven, innovative, and readily available method of treating inflammatory bowel disease.

Applications

·Commonly available and Low safety risk Citrulline and Fisetin are already available and used by the general public as nutraceuticals.

Advantages

Technology's Essence

The Erez lab studied nitric oxide (NO), an important signaling molecule that participates in various physiological and pathological conditions. Arginine, the substrate for NO production, is uniquely synthesized by Argininosuccinate lyase (ASL). The team performed cell-specific knockouts of ASL in different cells of varying colitis mouse models to discover the contribution of NO production in relation to disease progression. These experiments revealed that in the context of colitis, NO is a double-edged sword; NO production by enterocytes alleviates colitis while NO production by immune cells increases colitis severity. Induction of NO synthesis in enterocytes by upregulating ASL or Fisetin, as well as adding supplements which support NO production, such as Citrulline, ameliorated colitis and inflammation-related colon cancer.

As the worlds population grows, and climate changes, there is a strong need for breeding hardier crops in a precise fashion. The traditional method of introducing new traits to a plant via traditional breeding methods is a slow and stochastic process, which can require growing a large number of plants...

As the worlds population grows, and climate changes, there is a strong need for breeding hardier crops in a precise fashion. The traditional method of introducing new traits to a plant via traditional breeding methods is a slow and stochastic process, which can require growing a large number of plants to screen for desired progeny. Additionally, it can be difficult to generate a new variety with only the desired traits without any extra undesired traits being introduced in the process. The reason being is the randomness of genetic recombination during reproduction and due to the genetic linkage between desirable and undesirable traits. Therefore, it would be of great value to precisely shuffle genetic elements between chromosomes in both somatic and meiotic plant cells at specific sites.

The group of Prof. Avi Levy have recently devised a method for inducing site specific recombination between homologous chromosomes using CRISPR/Cas9. The technology has numerous applications including allelic replacement in somatic cells. As well as performing reciprocal exchanges of large homologous chromosomal segments at specific locations, enabling recombination events that are rare via traditional breeding. The technology also has great promise in relation to the regulatory environment; as the USDA has stated that it would not oversee multiple crops that were gene edited by CRISPR/Cas9[1]. Consequently, this technology has great value as a method for combining specific crop traits and for improving the accuracy of plant breeding in plants.

Applications

?Inducing targeted Homologous Recombination

?Improving Plant Breeding  through a higher precision of the exchange of chromosomal segments and through the use of smaller populations

?Applicable with any nuclease system  Simply requires that the system generates a DSB in somatic cells of a hybrid plant. (e.g. TALENs, CRISPR/Cas9, )

Advantages

The research team led by Prof. Avi Levy at the Weizmann Institute of Science has developed a method to site specifically induce homologous recombination (HR) between chromosomes. The team has applied the innovation in tomato and in Arabidopsis plants. CRISPR/Cas9 was used to perform site specific double strand breaks (DSB) on homologous chromosomal sections. Then using a series of phenotypic and molecular assays, the Levy team could show the DSB repair events were due to HR (either crossover or non-crossover) rather than non-homologous end joining (NHEJ).

THE INNOVATION: A non-chromatographic antibody purification method not relying on Protein A nor any ligand, had been developed. Highly pure (>95%) human, mouse, rabbit or sheep IgG's are obtained in good yields within 20-30 minutes. The technology addresses a projected $440M antibody purification...

THE INNOVATION:

A non-chromatographic antibody purification method not relying on Protein A nor any ligand, had been developed. Highly pure (>95%) human, mouse, rabbit or sheep IgG's are obtained in good yields within 20-30 minutes. The technology addresses a projected $440M antibody purification reagents market.

MARKET OPPORTUNITY:

The past two decades have evidenced a strong focus on monoclonal antibody (mAb) therapeutics. Today, there are already 50 antibody-based drugs on the market; more than 550 are at various stages of development; and the competition among the large biopharmaceutical companies is aggressive. The global market for mAb therapeutics in 2014 reached USD 80.3 billion. The global mAb market is expected to rise at a compound annual growth rate (CAGR) of 8.1% to nearly USD 128 billion by 2020. The development of these new molecular agents, successfully directed to specific cellular targets, is playing a crucial role in the pharmaceutical industry. This trend shows the strong focus of top biopharmaceutical companies on biologics, including mAb therapeutics (Frost & Sullivan 2015).

Accordingly, the rapid growth of the mAb market is driving pharmaceutical firms to find avenues that will reduce production costs. Purification of mAb's, is still a major contributor (50-80%) of manufacturing costs, particularly due to the use of Protein A columns. Whereas Protein A is the most efficient, specific and common ligand used by all biopharmaceutical companies, it is also highly expensive. It is estimated that removal of the Protein A step would cut 40% in the total production costs of mAb's and this is exactly what our technology is aiming at.